Cardiovascular disease (CVD), osteoporosis, and diabetes are exceedingly common in older persons, and are responsible for substantial morbidity and mortality. Mechanisms responsible for their development are not fully elucidated. There are overlaps in the pathways to each. Exploring mechanisms at points in the pathways common to each will provide novel insights to the biology leading to each disease, and may ultimately lead to novel therapeutic targets for their prevention. Fetuin-A is a hepatic secretory protein with the principal function of regulating calcium and phosphorus deposition in the vasculature and bone. Fetuin-A also directly and indirectly induces peripheral insulin resistance. We have made major contributions to defining the epidemiology of fetuin-A and elucidating its role in the development of subclinical CVD, bone disease, and diabetes in human populations. While these preliminary studies have provided important new insights, much of the existing data has been cross-sectional, and therefore the temporal relationship of fetuin-A with disease outcomes is largely unproven. This application will determine the prospective associations of fetuin-A with CVD mortality, fractures, and diabetes in older persons. The study will be efficiently conducted as a nested study within the Rancho Bernardo Study;an established observational cohort among community living older persons. The study will make fetuin-A measurements on stored blood specimens from 1992-96. Subjects have been followed longitudinally from that time forward, providing over 15 years of follow-up for CVD mortality, osteoporotic fractures, and incident diabetes. We will utilize this rich resource to: (1) Determine whether fetuin-A levels are associated with cardiovascular disease;(2) Determine whether fetuin-A levels are associated with incident osteoporotic fractures;and (3) Determine whether the association of fetuin-A levels with incident diabetes mellitus is mediated through adiponectin and longitudinal changes in body fat, in community-living older persons. PUBLIC HEALTH RELEVANCE: While cardiovascular disease, osteoporosis, and diabetes represent common and morbid disease in older persons, our understanding of their pathogenesis remains incomplete. The results of this epidemiologic study will provide novel insights into their pathogenesis and may ultimately identify novel therapeutic targets for their prevention or treatment.